Alzheimer's disease (AD), also named senile dementia, is a type of neurodegenerative disease. With the acceleration of population aging process, senile diseases have become outstanding problems affecting human health. Senile dementia, malignant tumors and cardio-cerebrovascular accident are three leading diseases which cause the death of the elderly. World Health Organization has listed AD as one of the five major diseases in the 21st Century.
Modern medicine has proved that the major pathological changes of AD have the following features: a great number of senile plaques (SP) formed among nerve cells due to the deposition of β-amyloid peptide (Aβ); neurofibrillary tangle (NT) in nerve cells; and extensive neuron loss. Currently, the theory of β-amyloid protein is predominant in the understanding of AD pathogenesis. In this theory, it is believed that the pathological fold of Aβ and the formation of oligomer initiate the onset process of AD, such as the formation of oxygen free radical, oxidative stress, the destruction of intracellular calcium ion homeostasis, the activation of protein kinases, the hyperphosphorylation of tau protein, the induction of apoptosis, chronical inflammation, complement activation, and the influence on mitochondrial function, which lead to pathophysiological changes such as energy metabolism disorders and finally the death of nerve cells, thereby causing a series of clinical symptoms in AD patients, such as memory loss, the decline of cognitive performance, and abnormal behaviors.
A lot of evidences indicate that the neurotoxic effect of Aβ is the common pathway of AD pathogenesis caused by various factors, and the neurotoxicity of Aβ is associated with its aggregation. In the secondary structure of Aβ, the formation of β-sheet is essential for Aβ aggregation, while β-sheet abundant structures can promote Aβ aggregation more quickly. The formation of β-sheet is associated with the hydrophobic fragments in Aβ peptide chains. Under certain conditions, the exposure of hydrophobic regions in β-sheet abundant structures will promote Aβ aggregation, oligomer formation, and eventually the formation of insoluble materials deposited in the intercellular space of neurons. This may result in neurotoxicity and the increased activities of glial cells in the brain, producing inflammatory mediators and complements which may together form amyloid plaques. Research found that the level of soluble Aβ ingredient has a closer relationship with the severity of cognitive impairment than the density of plaque deposition. Different Aβ soluble oligomers, such as Aβ oligomer, ADDLS and Aβ fiber, may affect neurological functions and neurological viability by different neurotoxic mechanisms (Deshpande A, Mina E, Glabe C. Different Conformations of Aβ Induce Neurotoxicity by Distinct Mechanisms in Human Cortical Neurons[J]. J Neurosci, 2006, 26(22):6011-6018).
As the main ingredient of senile plaques, Aβ is a metabolite of the hydrolysis of amyloid precursor protein (APP) by β- or γ-secretase. Whether Aβ1-40 or Aβ1-42 is produced depending on the enzymatic cleavage sites. Compared with Aβ1-40, Aβ1-42 has higher neurotoxicity and hydrophobicity, is more prone to form oligomers and further aggregate, and thus plays a key role in AD pathological process.
The primary structure of Aβ1-42 peptide is shown as follows (SEQ ID NO: 3):
Asp-Ala-Glu-Phe-Arg-His-Asp-Ser-Gly-Tyr-Glu-Val-His-His-Gln- 1               5                  10                   15 Lys-Leu-Val-Phe-Phe-Ala-Glu-Asp-Val-Gly-Ser-Asn-Lys-Gly-Ala-16               20                 25                   30 Ile-Ile-Gly-Leu-Met-Val-Gly-Gly-Val-Val-Ile-Ala31               35                 40       42
The ten amino acid residues 33-42 at C-terminal and amino acid residues 17-21 of Aβ1-42 are highly hydrophobic and constitute the hydrophobic regions of Aβ1-42. Amino acid residues 28-42 are more likely to form a β-sheet conformation, and amino acid residues 9-21 may also form a β-sheet conformation. β-sheet conformation is favorable to Aβ1-42 peptide aggregation, which results from the interaction between its hydrophobic regions. Using spectroscope and cellular technologies, M Q Liao et al. find the hydrophobic fragments of amino acid residues 17-21 and 25-35, and amino acid residues 41-42 at C-terminal of Aβ1-42 peptide chain are the main regions which cause aggregation and neurotoxicity (Liao M Q, Tzeng Y J, Chang L Y, et al. The correlation between neurotoxicity, aggregative ability and secondary structure studied by sequence truncated Abeta peptides[J]. FEBS Lett, 2007, 581(6):1161-1165).
The object of recent studies on the drugs against Aβ is reducing Aβ formation, increasing Aβ clearance, preventing or reversing Aβ aggregation, and inhibiting Aβ toxicity, and so on. Researchers from the Medicine School of Washing University (US) surprisingly found that the brain cells of AD mice start to restore functions after the amyloid protein plaques in their brains are removed, which indicates a promising prospect of the drugs against Aβ. Among various drugs against Aβ, β-sheet blocking agents draw increasing attention of researchers.
Chinese patent CN 101531703A discloses a few of polypeptides which can specially bind to Aβ1-42, stabilize its normal spatial structure, inhibit the formation of β-sheet, prevent the formation of soluble β-amyloid protein oligomers and β-amyloid protein plaques, and degrade Aβ fibers. These polypeptides are named β-sheet blocking peptides. After comparison, it is found that the polypeptide having the sequence of His-Lys-Gln-Leu-Pro-Phe-Phe-Glu-Glu-Asp (H102) (SEQ ID NO:2) has the strongest inhibition on Aβ aggregation (inhibitory rate: 27.84%).
In the art, there are still requirements for new active drugs which are designed to better target at the essential β-sheet in Aβ aggregation. Said drugs can specially bind to β-amyloid protein monomer (AB1-42), prevent the formation of β-sheet and further inhibit Aβ peptide aggregation, reduce the formation of Aβ soluble oligomer, Aβ fiber and senile plaques in the brain, accelerate the degradation and removal of Aβ peptide, and accordingly can be used for prevention and/or treatment of AD.